The objective of this project is to uncover and describe naturally occurring delayed-type iso-hypersensitivities (DIH) towards heritable iso-antigens, to determine the function of DIH, and to seek health-oriented conditions controlled by DIH. Three instances of iso-reactivity have been described from this laboratory. In guinea pigs DIH can be detected by delayed dermal reactions to an iso-antigenic heritable serum factor. The other two, in mice, are revealed by T cells that replicate in the presence of mitomycin-treated, isogeneic adult spleen cells. We are concentrating attention on these latter two isogeneic lymphocyte interactions (ILI) by studying the B cells and their differentiation markers that stimulate the replication, the T cells that are caused to divide, and the immunological principles and health problems that are revealed by ILIs that occur both in vivo and in vitro. The first ILI (Type 1) is that in which neonatal thymus cells undergo blastogenesis in the presence of adult isogeneic splenic cells possessing a marker termed murine differentiation antigen-1 (MDA-1). In Type-2 ILI, adult lymphnode T cells divide when co-cultured with adult autologous or isologous spleen cells displaying MDA-2. Bone marrow cells have neither of the MDAs but acquire them with time in a splenic environment. The appearance of MDA-1 on such maturing cells correlates with the capacity of the cells to interact in an in vitro antibody system with T cell helper factor (TRF). Thus, this membrane structure may be a receptor for TRF. The importance of ILIs to the phenomenon of self-tolerance and to immuno-regulatory mechanisms cannot be overemphasized.